Tumor Necrosis Factor (TNF) is a critical mediator of SCI-induced neuroinflammation. TNF exists in two biologically active forms, soluble-TNF (solTNF) and transmembrane-TNF (tmTNF) that preferentially bind to TNFR1 and TNFR2, respectively, and elicit quite distinct biological responses. The overarching goals of this competitive renewal are to: 1) investigate the therapeutic potential of pharmacologically manipulating TNF signaling to develop a therapy for traumatic SCI; and 2) investigate the mechanisms through which TNFR2 signaling on astrocytes and oligodendrocytes is neuroprotective. In support of our first goal we have determined that delivering XPro1595 directly to the injured cord for just 3 days, beginning 1h post-trauma, significantly improved functional recovery and reduced tissue damage, for up to 5 weeks. In contrast, etanercept, an inhibitor of both solTNF and tmTNF, did not improve functional recovery or tissue damage when delivered directly to the cord. The systemic administration of XPro1595 or etanercept did not improve functional recovery or reduce tissue damage. Thus, we hypothesize that solTNF is toxic to neurons and oligodendrocytes. Further, inhibiting solTNF and promoting tmTNF signaling through TNFR2 within the cord is therapeutic and neuroprotective following SCI. In support of our second goal, we are using genetic strategies to selectively delete TNFR2 from astrocytes, oligodendrocytes and OPCs in vivo to investigate what effect this has on functional recovery and tissue damage. Using GFAPcreER-TNFR2f/f mice we provide evidence that deleting TNFR2 expression on astrocytes worsens functional recovery and tissue damage following SCI. Next, utilizing CNPcreTNFR2f/f and PDGFR?creTNFR2f/f we show that oligodendrocyte and OPC TNFR2 are not required for normal myelination during development. However following injury, there is significantly more myelin damage in CNPcreTNFR2f/f mice. Finally, we show in vitro that TNFR2 induced oligogenesis is dependent in part in the IRE1a/XBP1 signaling. Thus, we further hypothesize that TNFR2 signaling on glial cells plays very specific role in reducing damage and promoting functional recovery. These hypotheses and experimental objectives will be tested in the following specific aims: Specific Aim 1: Investigate the therapeutic potential of XPro1595 and TNC-sc-mTNFR2, on functional recovery, histopathology and neuroinflammation following SCI. Specific Aim 2: Investigate the role of TNFR2 signaling on astrocytes in functional recovery, histopathology, and neuroprotection. Specific Aim 3: A) Investigate the role of oligodendrocyte-TNFR2 and OPC-TNFR2 in remyelination, oligogenesis, neuroprotection and functional recovery following SCI and B) Investigate the mechanisms through which TNFR2 induces oligogenesis, in vitro.